It is generally accepted that hippocampal hyperexcitability and cell degeneration often co-exist in temporal lobe epilepsy. Dendritic spine loss and swelling are commonly displayed in epileptic tissue, and are also generated in some of the experimental models of epilepsy. A recent study in human epileptic hippocampal slices demonstrated a high incidence of epileptogenic synaptic transmission in neurons whose dendrites were pathologically altered. This evidence suggests that dendritic degeneration, characteristic of epileptic pathology, may not necessarily be accompanied by hypo-responsiveness to synaptic inputs. To the contrary, in the course of their pathological progression, such morphological changes may create a cellular environment that accelerates the neuronal excitability underlying in situ epileptic seizures. I plan to use the pilocarpine model for temporal lobe epilepsy to test the above hypothesis. Preliminary Studies show that the dentate granule cells (DGCs) in pilocarpine-treated rats display similar morphological alterations in their dendrites to those reported in human epileptic hippocampus, i.e. changes of spine shape, spine loss and irregular shafts due to swelling. Neurophysiological recording from these neurons revealed hyperexcitability in perforant path synaptic transmission. Using the techniques of intracellular recording, intracellular cell staining, whole cell patch clamp recording, and microapplication of neurotransmitter agonists in hippocampal slices, I will 1) determine the intrinsic membrane properties of the dendritically-deformed neurons, and 2) isolate excitatory and inhibitory post synaptic responses electrically and pharmacologically. The role of different synaptic currents will be assessed in generating increased synaptic responses in the pilocarpine-treated DGCs. 3) The effect of the NMDA EPSCs on the subsequent GABA-A IPSCs will be studied. In normal rat hippocampal slices, increased intracellular calcium concentration can down-regulate GABA-A receptor function. I will test this possibility in dendritically-degenerating DGCs where an increased NMDA response is observed. The increased NMDA response likely elevates intracellular calcium level abnormally, which possibly facilitates calcium's modulatory effect on GABA-A receptor function in pilocarpine-treated DGCs. In pilocarpine DGCs, GABA-A current may be temporarily lost when increased NMDA currents are generated. 4) Dendritic deformities will be quantified by counting the number of spines within defined segments and by measuring dendritic domains. These findings will be correlated with the above physiological findings. This determines the sensitivity of synaptic plasticity in dendritically degenerating neurons. Together, these experiments will provide evidence for a fuller understanding of the excitability of dendritically degenerating neurons in epilepsy.